Project Summary/Abstract Past work under this grant documented the existence of a peculiar type of mammalian ganglion cell that functions as an autonomous photoreceptor. These intrinsically photosensitive retinal ganglion cells (ipRGCs) use the invertebrate-like photopigment melanopsin. They encode ambient light intensity and help to drive various reflexive responses to daylight, such resetting the circadian clock and adjusting pupil diameter. Much of the work in the next grant period is inspired by two surprising lines of pilot evidence. First, we now believe that there is at least one additional type of intrinsically photosensitive ganglion cell. Second, we have evidence that signals from ganglion-cell photoreceptors propagate not only to the non-image-forming visual networks of the brain, but also within the eye itself to other retinal neurons. Targets appear to include certain ganglion cells and dopaminergic amacrine (DA) cells. The influence of ipRGCs on DA cells is apparently reciprocated, and we will study the mutual interactions between these cells in detail. DA cells and ipRGCs are further linked by the fact that both stratify in the same OFF sublamina of the IPL, yet receive a paradoxical synaptically driven ON input of unknown origin. Here, we will work to identify a neural circuit that could account for this input. The specific aims of the proposal are: 1) to characterize the structure and function of a new type of ganglion-cell photoreceptor; 2) to characterize the inputs to ipRGCs from dopaminergic amacrine cells and ON bipolar cells; and 3) to characterize the influences of ipRGCs on dopaminergic amacrine cells and other retinal neurons. These studies extend our understanding of the photoreceptive capacity that persists in human outer retinal degenerations such as retinitis pigmentosa. They also bear on fundamental mechanisms of circadian and adaptational modulation of retinal function. Project Narrative This project is to study the structure and function of specialized retinal cells that can independently detect light and regulate the biological clock, the amount of the hormone melatonin in the bloodstream, and the size of the eye's pupil. We want to explore the possibility that there are more varieties of such cells than previously recognized and to understand the reciprocal interactions between these cells and other retinal neurons. Because of the key role these cells play in the body's responses to daylight, these studies are relevant to such public health issues as jet lag, seasonal affective disorder, circadian disruption in the blind, and the negative consequences of shift work including impaired performance, increased risk of injury and even elevated cancer rates.